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Summary:Purpose: A double-blind, randomized, placebocontrolled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.Methods: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner.Results: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. KaplanMeier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc x' probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group.Conclusions: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity. Key Words: Ganaxolone-Epilepsy-Presurgical trial-Partial seizures-y-Aminobutyric acid A modulator.Ganaxolone is a member of a novel class of neuroactive steroids called epalons, which allosterically modulate the y-aminobutyric acid type A receptor complex via a unique recognition site (1). The compound was developed after it was observed that endogenously occurring metabolites of progesterone and deoxycorticosterone, such as 3a-hydroxy-501-pregnan-2O-one and 501-tetrahydrodeoxycorticosterone, had substantial anticonvulsant effects in animal models of epilepsy (24). Ganaxolone (3au-hydroxy-3~-methyl-5a-pregnan-20-one) is the 3P-methylated, synthetic analog of 301-hydroxy-501-pregnan-20-one and possesses no detectable hormonal acAccepted May 12, 2000. Dr. Morrell is now with The Neurological Institute, Columbia Presbyterian Medical Center, New York, NY.Address correspondence to Dr. Edward P. Monaghan at Serono, Inc., 700 Longwater Dr, Norwell, MA 02061. E-mail: edward.monaghan. us-bos0 1 @ serono.com tivity (5). In vivo pharmacology studies demonstrated that ganaxolone provides protection in a wide variety of animal models, including pentylenetetrazol-, bicuculline-, aminophylline-, t-butylbicyclophosphorothionate-, and corneal kindling-induced seizure models, suggesting that it may have utility in the treatment of a broad range of seizure types (6-8).Traditionally, early clinical trials in epilep...

Ganaxolone is a member of a novel class of neuroactive steroids which modulates the GABA(A) receptor complex (GRC) via an unique recognition site, distinct from those of benzodiazepines and barbiturates. Preclinical data from an array of chemically- and electrically-induced seizure models demonstrate that ganaxolone possesses broad spectrum anticonvulsant activity with potential clinical utility in both generalised and partial seizures, as well as cocaine-induced seizures. Clinical data to date support a favourable safety profile with somnolence, an extension of GABAergic activity, being the most frequently reported adverse event at higher doses. Target indications include infantile spasms and complex partial seizures. Open-label data in paediatric patients with intractable epilepsy suggest that ganaxolone may be effective in treating infantile spasms. A controlled trial utilising an in-patient, monotherapy design demonstrated that ganaxolone effectively decreases complex partial seizure activity compared to placebo. An important area of further evaluation is ganaxolone's potential role in the treatment of women with catamenial epilepsy.

Background and Purpose-Licostinel (ACEA 1021; 5-nitro-6,7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke. Methods-In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale. Results-Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated.Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models. A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients. Conclusions-A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients.Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists. (Stroke. 1999;30:508-513.)